Heart failure occurs when the heart is unable to pump sufficient blood to meet the body's needs. Until relatively recently, research and treatment has focused on left ventricular failure (or left heart failure). In fact, generally the term heart failure has been used when referring to left ventricle dysfunction and/or congestive heart failure. More recently the importance of the right ventricle in heart failure has been recognized; however treatments for right ventricular dysfunction are lacking.
The right ventricle (RV) is structurally different from the left ventricle (LV). For instance, the left ventricle is more muscular, being responsible for receiving oxygenated blood from the left atrium and pumping it through the aorta at relatively high pressures into the systemic circulation, supplying blood to all organs and tissues of the body. In contrast, the right ventricle receives deoxygenated venous blood from all organs and tissues of the body through the right atrium, and pumps the blood, representing the entire cardiac output, to a single organ—the lungs—at remarkably low pressures. In addition, the RV is derived from a different set of precursor cells, has a more complex 3D morphological shape, usually operates at much lower pressures (afterload), and has a distinct contraction pattern. Given the different structure of the right ventricle and that it operates under different hemodynamic conditions, it is not surprising that the RV responds differently to loading conditions, like chronically elevated pressure (afterload). Pressure overload refers to the pathological state of cardiac muscle resulting from having to contract while experiencing an excessive afterload (pressure). The most common causes of RV pressure overload are pulmonary valve stenosis and pulmonary hypertension (PH) from any cause.
Pulmonary hypertension (PH) is characterized by increases in pulmonary arterial pressure and therefore RV systolic pressure (RVSP), and has been classified into 5 groups (the WHO classification) as follows:                Group 1, pulmonary arterial hypertension (PAH);        Group 2, PH due to left heart disease and elevated LV filling (venous) pressures;        Group 3, PH due to lung diseases and/or hypoxia;        Group 4, chronic thromboembolic PH; and        Group 5, PH with unclear multifactorial mechanisms.        
Cardiac ventricular remodeling refers to changes in size, shape, structure, and physiology of the main pumping chambers of the heart. In response to increased ventricular afterload (myocardial wall tension during systole), individual cardiomyocytes increase in size (i.e. myocyte hypertrophy), the myocardium thickens (myocardial hypertrophy) to normalize ventricular wall tension (therefore afterload), thereby eliminating the initial stress and maintaining normal cardiac output to meet the systemic demands of the body. One aspect of ventricular remodeling, namely ventricular hypertrophy, relates to the thickening of the ventricular walls (pumping chambers) in the heart. These remodeling responses can be either physiological (adaptive/beneficial/compensatory) or pathological (maladaptive/harmful/adverse/noncompensatory) and are associated with distinct structural changes in heart (at the gross morphologic and cellular level), and differences at the molecular level in gene expression and signal transduction pathways.
Pathological (or maladaptive) cardiac remodeling is a progressive form of organ growth, whereby initial contractile improvements are rapidly curtailed by unrestrained enlargement of the myocardium proper. New sarcomeres are added in-parallel with existing sarcomeres (i.e. the cardiomyocytes thicken rather than lengthen) in response to chronic pressure overload. This type of remodeling is also termed concentric remodeling. Thus, the cardiac wall thickens and the chamber volume is initially maintained or reduced. However, the right ventricle cannot sustain long term pressure overload, and RV pathological cardiac remodeling is eventually characterized by an increase in the size of the RV chamber (RV dilation) and reduced contractile function.
Adaptive compensation or physiological cardiac remodeling is a beneficial form of myocardial growth, arising from a compensatory response to conditions that require increased blood volumes such as pregnancy and chronic aerobic exercise training. Dissimilar to pathologic remodeling, physiologic growth of the myocardium is characterized by enhanced cardiac function and modest increases in ventricle dimensions. If the precipitating stress is volume overload (as through aerobic exercise, which increases venous return to the heart through the action of the skeletal-muscle pump), the cardiac muscle responds by adding new sarcomeres in-series with existing sarcomeres (i.e. the cardiomyocytes lengthen more than thicken). This type of growth is also termed eccentric hypertrophy. An essential hallmark of physiologic hypertrophy that distinguishes this form of growth from pathologic hypertrophy is the reversibility of the cell growth, whereby the removal of the stimulus leads to a complete reversion of the adaptation.
Functional limitations and prognosis in PH (regardless of the Group) is determined largely by the degree to which the RV can adapt to increased RV pressure and afterload. If the RV can remodel in a compensatory manner and maintain its systolic function, then even severe PH can be well tolerated. However, if the RV is unable to adapt to increasing afterload, it will undergo noncompensatory remodeling characterized eventually by an increase in the size of the RV chamber (RV dilation) and reduced contractile function. In other words, a decrease in RV function will lead to a lack of oxygen perfusion as the pumping of blood to the lungs with its concurrent oxygenation will decrease (among other problems). This leads to clinical symptoms and signs of right heart failure (RVF or RHF), with progressive limitation in the ability of the right heart to accommodate increases in cardiac output (CO) during exercise (shortness of breath on exertion, SOBOE) and ultimately even at rest (NYHA class IV heart failure). Deteriorating RV function and dropping CO can also lead to a drop in the systemic arterial blood pressure during exercise that results in presyncope and syncope (fainting), a characteristic symptom of advanced PH, and ultimately death. In other words, a progressive right heart failure develops owing to the sustained RV pressure overload. The disease course has been characterized as consisting of an early, “compensated” stage associated with right heart physiological remodeling but normal RV diameter and function, followed by transition to a decompensated state (pathological remodeling) characterized by increasing RV dilatation and worsening contractile function. Therefore, survival of patients with PH is closely related to RV function. In fact RV failure is the cause of at least 70% of deaths attributable to PH.
Despite its importance, until recently the right heart has not received the same degree of research interest as other aspects of PH, and relatively little is known about the mechanisms of right ventricular failure in PH, or the prognostic implications of specific changes in right ventricular structure and function. Pathological right ventricular remodeling has significant prognostic and therapeutic implications to patients with PH. Unfortunately, the pharmacological therapies developed over the last 30 years for the treatment of left heart failure (e.g. congestive heart failure), are not effective in the treatment of RV failure. PAH therapies primarily target the pulmonary vascular abnormalities (primarily vasoconstriction and arterial remodeling), and none of these were designed to directly benefit the right ventricle (RV). In fact, medications for PAH that affect the pulmonary vasculature, may be detrimental to the right heart. Because a patient's functional state and prognosis are largely determined by performance of the RV, there is a need for a treatment for PH which improves the ability of the right ventricle to adapt to increased afterload. Thus, novel therapeutic approaches are urgently needed.
CT-1 expression has recently been associated with an array of cardiac pathologies including: hypertension, myocardial infarction, and heart failure (Jin et al. 1996 Cytokine 10:19-25, Calabro P. et al. 2009 J Mol Cell Cardiol. 46(2):142-8, Schillaci G. et al. 2013 J Hypertens 31 474-76, Lopez B. et al. 2014 Hypertension 63:483-89). Although these disease studies linked CT-1 to a pathologic outcome, the observations were associations rather than true cause and effect experimentation. Indeed, while some studies associate circulating CT-1 levels with cardiac pathologies, other studies could not confirm these findings (Zile M R et al. 2011 Circ Heart Fail 4:246-56).